p27 binds cyclin-CDK complexes through a sequential mechanism involving binding-induced protein folding

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• The protein p27 (also known as CDKN1B) is a key regulator of cell proliferation.
• It functions by inhibiting nuclear cyclin-dependent kinases (CDKs), which are critical for cell cycle progression.
• p27 also interacts with various other cellular targets, indicating diverse biological roles.

Purpose of the Study:

• To elucidate the structural and dynamic properties of p27 that underpin its multifaceted functions.
• To understand the molecular mechanisms by which p27 interacts with its targets, particularly CDK-cyclin complexes.

Main Methods:

• Investigated the structural characteristics of p27, including its intrinsic disorder and nascent secondary structure.
• Utilized kinetic analyses to determine the mechanism of p27 binding to Cdk2-cyclin A.
• Examined the specificity of p27 interactions with different CDK-cyclin complexes.

Main Results:

• p27 exhibits intrinsic disorder but possesses nascent secondary structure that may aid in molecular recognition.
• Binding to Cdk2-cyclin A induces p27 folding, with kinetics suggesting an initial interaction with cyclin A.
• p27 specifically targets CDK-cyclin complexes involved in cell cycle control, not closely related CDKs.

Conclusions:

• p27's interaction with cyclin A is crucial for its specificity and function in regulating cell cycle progression.
• The findings suggest a sequential, folding-on-binding mechanism for p27's activity.
• Homologous proteins p21 and p57 likely employ similar mechanisms for their cell cycle regulatory functions.